Background Gastrointestinal stromal tumors (GIST) are very rare in the pediatric population, affecting less than 100 children yearly. The rarity of this tumor has precluded the ability to perform systematic clinical and research studies, and treatment regimens have varied widely from one institution to another. The lack of patients has also led to the reliance of case reports as the extent of the published literature. In order to mitigate these deficiencies, the Pediatric Oncology Branch of the National Cancer Institute and the Pediatric Endocrinology Unit of the National Institute of Child Health and Human Development have collaborated to initiate the NIH Pediatric and wildtype GIST Clinic. This is a bi-annual clinic that brings children and young adult GIST patients together with some of the leading clinicians and researchers in the field of GIST. In 2008, we held the inaugural NIH Pediatric and wildtype GIST Clinic, which was very successful. We also opened our website and included a dedicated e-mail address for correspondence. In 2009, we completed the 2nd and 3rd NIH Pediatric and wildtype GIST Clinics and 39 patients attended. Based on the medical information that we collected, we started issuing guidelines for management, including treatment with tyrosine kinase inhibitors, preferred imaging modality, follow-up schedule, and ancillary studies to address potential complications due to treatment side effects. These results were presented at the annual 2009 Connective Tissue Oncology Society conference in Miami. Results from 2010 In 2010, we completed the 4th and 5th NIH Pediatric and wildtype GIST Clinics and 58 patients have participated. As we continued to gain value data relating to clinical parameters, we also increased our research endeavors. We published a review article detailing the biology of GIST and our plans to further understand its pathogenesis, Pediatric and wildtype gastrointestinal stromal tumor: new therapeutic approaches in Current Opinion in Oncology. We identified germline mutations in subunits of the succinate dehydrogenase gene in 15% of our younger patients. We are currently testing available tumor samples for loss of the associated chromosome regions to demonstrate functional loss of both copies of these subunits. Concurrently, we have also shown complete loss of SDHB in younger GIST patients by western blot analysis, suggesting that disruption of genes in this pathway plays an important role in this disorder. These results were presented at the annual 2010 American Society of Clinical Oncology conference in Chicago. A manuscript detailing these findings has been submitted to the journal Proceedings of the National Academy of Sciences USA. We have also collaborated with members of Dr. Paul Meltzers laboratory who have identified activating mutations in the BRAF gene in 15% of our older patients. CLIA certification of these mutations has been performed and these results were relayed to the primary oncologist. One patient has since started on a clinical trial with an inhibitor that is specific for BRAF. The ability to quickly translate our research findings to place patients onto clinical trials was our vision of how this clinic would operate. We are preparing a manuscript detailing these findings. Plans for 2011 In 2011, we have the following specific objectives for the NIH Pediatric and wildtype GIST Clinic. .1. Continue with the 6th and 7th clinics to allow more patients to undergo evaluation .2. Continue germline SDH mutation analysis and assess downstream elements, such as HIF-1alpha, that may be amenable to therapy .3. Continue BRAF mutation analysis and examine MEK and MAPK activation as other potential targets for therapy .4. Continue to examine EGFR expression status and attempt to correlate high expression with genomic amplification .5. Continue to collect fresh tissue for establishment of cell lines and murine xenografts .6. Begin next generation sequencing on flash frozen tumor and normal blood samples .7. Begin collaboration to perform miRNA analyses of pediatric versus adult wildtype samples .8. Begin collaboration to perform comparative genomic hybridization to assess global genomic changes Significance and Goals The successful completion of the above objectives will allow us to continue to build on the wealth of knowledge about the natural history of pediatric GIST. Further examination of genes that are thought to play a role in this disease will allow us to continue to translate our research findings into the clinic by placing patients into a suitable clinical trial. The success of this clinic to date has allowed us to perform the preparatory steps for bold and innovative research studies, including global assessment of genetic stability, examination of the importance of miRNA in this disorder, and next generation sequencing. Our hope is that the successful completion of the above research objectives will propel the design of innovative national protocols for the treatment of patients with GIST. We believe that our clinic has proven to be an excellent model of how to study rare diseases. Papers and Presentations in 2010 Kim SY, Janeway K, Pappo A. Pediatric and wild-type gastrointestinal stromal tumor: new therapeutic approaches. Curr Opin Oncol 2010;22:347-350. PMID 20485167. Janeway KA, Kim SY, Lodish M, Nose V, Dahia P, Rustin P, Demetri GD, Fletcher JA, Helman LJ, Stratakis CA, Consortium for Pediatric and Wildtype GIST Research (CPGR). Succinate dehydrogenase in KIT/PDGFRA wild-type gastrointestinal stromal tumors. J Clin Oncol 2010;28supp:#10008.